title: N- versus O-alkylation: utilizing NMR methods to establish reliable primary structure determinations for drug discovery.
abstract: A classic synthetic issue that remains unresolved is the reaction that involves the control of N- versus O-alkylation of ambident anions. This common chemical transformation is important for medicinal chemists, who require predictable and reliable protocols for the rapid synthesis of inhibitors. The uncertainty of whether the product(s) are N- and/or O-alkylated is common and can be costly if undetermined. Herein, we report an NMR-based strategy that focuses on distinguishing inhibitors and intermediates that are N- or O-alkylated. The NMR strategy involves three independent and complementary methods. However, any combination of two of the methods can be reliable if the third were compromised due to resonance overlap or other issues. The timely nature of these methods (HSQC/HMQC, HMBC. ROESY, and (13)C shift predictions) allows for contemporaneous determination of regioselective alkylation as needed during the optimization of synthetic routes.
authors.affiliation: Department of Chemistry, Boehringer Ingelheim (Canada) Ltd, 2100 Cunard St., Laval, Quebec H7S 2G5, Canada. stevenrlaplante@gmail.com
authors.forename: Steven R
authors.initials: SR
authors.lastname: LaPlante
authors.forename: François
authors.initials: F
authors.lastname: Bilodeau
authors.forename: Norman
authors.initials: N
authors.lastname: Aubry
authors.forename: James R
authors.initials: JR
authors.lastname: Gillard
authors.forename: Jeff
authors.initials: J
authors.lastname: O'Meara
authors.forename: René
authors.initials: R
authors.lastname: Coulombe
mesh_terms: D000478:Alkylation; D018360:Crystallography, X-Ray; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000737:chemistry*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D009584:Nitrogen / Q000737:chemistry*; D010100:Oxygen / Q000737:chemistry*
chemical_list: D004791:Enzyme Inhibitors; D054303:HIV Reverse Transcriptase; D009584:Nitrogen; D010100:Oxygen
keywords: Drug discovery; Medicinal chemistry; NMR; O/N alkylation; Primary structure